Parkinsonism and Related Disorders 9 (2002) 29–38
www.elsevier.com/locate/parkreldis
Review
The natural history of sex-linked recessive dystonia parkinsonism of
Panay, Philippines (XDP)q
Lillian V. Lee*, Elma Maranon, Cynthia Demaisip, Olivia Peralta, Ruth Borres-Icasiano,
Jose Arancillo, Corazon Rivera, Edwin Munoz, Kenneth Tan, Marita T. Reyes
Office of the Executive Director, Child Neuroscience Division, Department of Health, Philippine Children’s Medical Center, Quezon Avenue,
Quezon City, Philippines
Abstract
Sex-linked dystonia parkinsonism (XDP) was reported by Lee et al. in 1975 occurring endemically in Panay, Philippines. It is an adult
onset, sex-linked, predominantly male, severe, progressive movement disorder with high penetrance and a high frequency of generalization.
The movement disorder is characterized by dystonic movements usually starting in the third or fourth decade, focal at the onset, spreading to
generalization within 2 – 5 years. The dystonia co-exist or is replaced by parkinsonism usually beyond the 10th year of illness.
As of June 2001, 376 XDP cases have been registered. One hundred and fifteen cases have died. The prevalence of XDP in the island of
Panay is 5.24 per 100,000; 0.34/100,000 in the general population. The prevalence varies in the different provinces; it is highest in Capiz at
18.88/100,000, 7.46/100,000 in Aklan, 1.28 in Iloilo and 0.83 in Antique. The 376 cases are from 188 families and 92% of cases have positive
family history. Ninety-nine percent of the cases are males. The mean age of onset is 39.48 years. Duration of illness is 12.95 years. Ninetyfour percent of patients initially manifest with dystonic symptoms, while only 6% present with Parkinsonian traits. Among those presenting
with dystonia, the initial presentation is in the lower extremities in 33%, craniofacial in 27%, cervical and shoulder in 25%, upper extremities
in 14%, and trunk in 1%. Regardless of the site of onset, the dystonia spreads in 98% and generalizes within 5 years in 84%.
Neuroimaging (magnetic resonance imaging, MRI) was done in 16 patients. In the patients who have just manifested the disease usually
when dystonia predominates and parkinsonism is absent. MRI showed minimal atrophy of the caudate and putamen or subtle putaminal
signal abnormality. In the late course, where Parkinsonism predominates, severe atrophy of the caudate and putamen as well as marked
increase in signal abnormality are seen.
There are six autopsied cases of XDP. Neuropathology revealed marked atrophy of the caudate and putamen mostly in the cases with
longstanding illness.
The sex-linked pattern of inheritance has been established. Genetic studies have located the affected gene (DYT3) to Xq13.1. Nemeth’s
group has mapped the XDP gene to a ,350 kb locus in the DXS 7117-DX 559 region.
To date, no treatment has been proven consistently effective. q 2002 Published by Elsevier Science Ltd.
Keywords: Dystonia; Parkinsonism; Sex-linked recessive XDP; Movement disorder; Filipino XDP; Lubag
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Demographics and statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Course of XDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Diagnostic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. Positron emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Discussion and summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
q
The authors would like to acknowledge the assistance of Ma. Imelda M. Lagula in the preparation of this manuscript.
* Tel.: þ63-2-924-08-36/65; fax: þ63-2-924-08-40.
E-mail address: [email protected] (L.V. Lee).
1353-8020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
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L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
Table 1
Demographics and clinical features
Variable
Data
No. of XDP cases registered from 1975 to 2001
No. of survivors as of June 2001
Philippine population as of 2001
Prevalence of surviving cases per 100,000
Prevalence of cases in Panay Island per 100,000
Prevalence of cases in Capiz per 100,000
Prevalence of cases in Aklan per 100,000
Prevalence of cases in Iloilo per 100,000
Prevalence of cases in Antique per 100,000
Prevalence of cases in Guimaras per 100,000
No. of families
No. of cases with positive family history
No. of deaths
Autopsied cases
Sex, male/female (%)
Age at onset, year; mean (range)
Age at initial exam, year; mean (range)
Duration of illness from onset to present, year; mean (range)
Duration of illness from onset to generalization of dystonia, year; mean (range)
Duration of illness from onset to parkinsonism, year; mean (range)
Age of survivors, year; mean (range)
Age at death, year; mean (range)
No. of XDP—initially presenting with parkinsonism, n (%)
No. of XDP—initially presenting with dystonia, n (%)
Lower extremities
Craniofacial
Cervical and shoulder
Upper extremities
Trunk
No. of cases, spread, n (%)
No. of cases, generalized, n (%)
No. of cases, parkinsonian, n (%)
Degree of disability of survivors, n (%)
No. still working
No. ambulant, not working
No. non-ambulant; able to care for self
No. wheelchair and bed bound
376
261
76.8M
0.34
5.24
18.88
7.46
1.28
0.83
0.71
188
344
115
6
372 (99)/4 (1)
39.48 (12–64)
40.8 (20–70)
12.95 (1–41)
3.8 (1–23)
13.39 (7–25)
52.56 (28–86)
51.36 (31–81)
24 (6)
352 (94)
123 (33)
102 (27)
94 (25)
52 (14)
5 (1)
369 (98)
316 (84)
53 (14)
11 (4)
188 (72)
3 (1)
59 (23)
XDP Philippine registry 2001.
1. Introduction
Sex-linked recessive dystonia parkinsonism (XDP) is a
movement disorder first reported in 1975 on patients from
the island of Panay, Philippines.
Dr George H. Viterbo, of Roxas City, Capiz (a province
of Panay) referred to the neurology section of the Philippine
General Hospital in the early 1970s, five of the six cases of
what then was rare ‘dystonia musculorum deformans’. This
initiated an epidemiologic survey, which resulted in the first
paper published in 1976 [1]. In the original paper, Lee et al.
described 28 adult male cases with torsion dystonia, from 25
families. There was no male to male transmission hence, the
inference of sex-linked recessive transmission. Some of the
patients were noted to have parkinsonian features and some
had relatives with parkinsonism. In 1991, the phenotype of
XDP was described in 42 male cases from 21 families [2].
Lee et al. emphasized that XDP manifest primarily as
dystonia in combination with parkinsonism. Fahn et al.
confirmed the co-existence of dystonia and parkinsonism in
XDP [3]. Fahn called the disease ‘lubag’ based on the term
used by the Ilongo speaking Filipinos to describe any
movement characterized by torsion including children with
cerebral palsy.
The natural history of XDP is now apparent. XDP is a
neurodegenerative movement disorder manifesting both
dystonia and parkinsonism. Presenting initially as a focal
dystonic movement mostly in an appendage, there is
spread of the disabling dystonic movements and generalization in 5 years. Subsequently, there is diminution of
dystonic movements, such that a parkinsonian-like state,
replaces the picture, usually beyond the 10th year of
illness. Bradykinesia, postural instability, festinating gait
and blepharospasm are the more common parkinsonian
features but rigidity and cogwheeling are infrequently
seen.
L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
31
Fig. 1. XDP patients manifesting generalized dystonia with prominent oromandibular features. (A) 53 years; ninth year of illness; onset 45 years. (B) 36 years;
12th year of illness; onset 24 years. (C) 46 years; sixth year of illness; onset 40 years.
2. Demographics and statistics
2.1. Course of XDP
Three hundred and seventy-six cases of XDP have been
registered with the Philippine XDP project based at the
Philippine Children’s Medical Center in Metro Manila and
in Roxas City, Capiz [4]. One hundred and fifteen have died.
The current prevalence rate is 0.34/100,000 population in
the Philippines. The prevalence rate is 5.24/100,000 (Table
1) in the island of Panay; however, in the different
provinces, Capiz has the highest rate at 18.9 cases/
100,000 population which translates to one per 4000
males. Aklan follows with a rate at 7.46/100,000. XDP is
considered endemic in Capiz.
The family history is positive in 94% of the 376 cases
belonging to 188 families. Forty-two kindred have more
than one affected sib with 39 families having more than two
brothers affected. Two sets of twins are recorded.
The male to female ratio is 93:1 (Table 1). Only males
were reported before 1992. The four females belong to three
families. Two are sisters. All had affected fathers and carrier
mothers. Waters et al. [5] reported two sisters with XDP,
ages 61 and 54, presenting with mild dystonia and chorea,
Waters’ cases did not progress whereas all three female
cases in our series, generalized.
The mean age of onset of XDP is 39.5 years ranging from
12 to 64 years (SD ^ 8.44) (Table 1). The female cases all
have onsets above 46 years.
Realizing that the initial area involved often predicts the
final outcome, i.e. generalization; the initial area of
involvement was particularly emphasized in all cases.
Out of the 376 XDP cases analyzed, only 24 had initial
parkinsonian symptoms in the form of foot tremor, hand
tremor or blepharospasm. Three hundred and fifty-two or
94% presented with focal dystonia at the onset. Focal
dystonia involving the lower extremities (bigtoe, dorsiflexion; foot inversion or tremor, gait dystonia) occurred in 123
(33% of cases). Blepharospasm, jaw opening and closing, or
tongue protrusion occurred in 102 (27%). Torticollis,
retrocollis, anterocollis, neck stiffness, tremors and shoulder
dystonia was the presentation in 94 or 25%. Tremors and
cramps of the upper extremities was the initial manifestation
in 52 or 14% of cases. Only five cases presented initially
with trunk flexion and extension or abdominal contractions.
The dystonia stayed focal for several weeks or months but
spread in 97% of all cases and generalized within 5 years in
84% (Table 1).
The dystonia progressed to involve the different areas of
the body such that the predominant picture was one of
severe, generalized, continuous contorting movements
while the patient is awake (Fig. 1). The movements
manifested the typical features of dystonia by their
consistent directional or posture assuming characters.
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L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
Table 2
Correlation of initial area of involvement and spread to generalization of dystonia and progression to parkinsonism XDP patients ðN ¼ 376Þ as of year 2001
Initial area of involvement
Lower extremities, n ¼ 123 (33%)
Duration of illness
(years)
Focal, n
(%)
Segmental, n
(%)
Multifocal, n
(%)
Generalized, n
(%)
Parkinsonian, n
(%)
,2
2– 5
5– 10
10– 15
.15
4 (80)
1 (20)
0
0
0
5
2 (15)
6 (46)
3 (23)
1 (8)
1 (8)
13
2 (28)
2 (28)
0
3 (44)
0
7
37 (52)
25 (35)
9 (13)
0
0
71
0
1 (4)
4 (15)
2 (7)
20 (74)
27
,2
2– 5
5– 10
10– 15
.15
0
0
0
0
0
0
1 (25)
1 (25)
1 (25)
1 (25)
0
4
0
2 (40)
1 (20)
2 (40)
0
5
13 (42)
14 (45)
3 (10)
1 (3)
0
31
0
0
1 (8)
2 (17)
9 (75)
12
,2
2– 5
5– 10
10– 15
.15
0
2 (67)
0
1 (33)
0
3
3 (25)
4 (33)
4 (33)
0
1 (9)
12
0
2 (50)
0
2 (50)
0
4
29 (45)
29 (45)
5 (8)
1 (2)
0
64
0
2 (18)
2 (18)
4 (36)
3 (28)
11
,2
2– 5
5– 10
10– 15
.15
0
0
0
0
0
0
1 (50)
1 (50)
0
0
0
2
0
0
0
0
0
0
1 (33)
1 (33)
1 (33)
0
0
3
0
0
0
0
0
0
,2
2– 5
5– 10
10– 15
.15
0
1 (50)
0
1 (50)
0
2
1 (6)
4 (25)
5 (31)
3 (19)
3 (19)
16
1 (20)
2 (40)
1 (20)
0
1 (20)
5
24 (38)
33 (52)
5 (8)
1 (2)
0
63
0
2 (12)
1 (6)
6 (38)
7 (44)
16
Total
Upper extremities, n ¼ 52 (14%)
Total
Cervical and shoulder n ¼ 94 (25%)
Total
Trunk, n ¼ 5 (1%)
Total
Craniofacial, n ¼ 102 (27%)
Total
Present status
One hundred and fifteen died; status of dystonia at time of death were considered.
Most of the dystonic movements were vigorous and rapid in
the early phase later slowing down. Some cases showed fast
choreiform and myoclonic like movements. Many patients
with XDP manifested sensory tricks which alleviated and at
times disguised the movements.
Table 2 correlates the initial area of involvement, the
duration of illness and the final distribution of the dystonia.
In this table, it is clearly shown that regardless of the site of
initial involvement, the final outcome was that of generalized dystonia and beyond the 15th year, parkinsonism. As
early as the second year, nearly 50% have generalized and
by the fifth year, 80% have generalized. The mean age of
generalization is 3.8 years from onset.
In most of the patients, there is an apparent decrease in
the severity of the movements, becoming less intense and
less rapid, as they approach the 10th year of illness. There is
subsequent plateauing in the severity and as observed in the
video recordings, gradually bradykinesia sets in and a
picture of stiffness appears. These patients, however, do not
show increase in tone; cogwheeling is rare and minimal
rigidity is noted. The parkinsonian features which are often
seen are festinating gait (shuffling), freezing, masked facies,
blepharospasm and bradykinesia. Beyond the 15th year of
illness, 53 cases have become parkinsonian with no signs of
the dystonia they had been suffering from, for years. The
mean duration of illness at which time parkinsonism is
reached is 13.39 years (Table 1). In the majority of cases,
however, the dystonic movements diminish and continue as
postural dystonia. As of 2001, from among the 261
survivors; only 11 (4%) are still able to work, 188 (72%)
are not working but ambulant and can care for themselves,
while 59 (23%) are wheelchair or bed bound.
The Fahn– Marsden Rating Scale (FMRS), Dystonia
Severity Scale (DSS) [6] and the Unified Parkinson’s
Disease Rating Scale (UPDRS) [7] were both utilized in
monitoring the severity of movements and degree of
disabilities. No electrophysiologic studies were done
prior to 1999 since most of the patients resided in
Panay. Recently, electromyography (EMG) was performed to document the movements. Most of the
L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
33
Fig. 2. A –D images demonstrate severe head atrophy with ex-vacuo dilatation of the frontal horns and severe atrophy of the putamina with ‘slit-like’ high
signal intensity on T2W and low signal intensity on T1W. Clinically, patient has both dystonia and parkinsonism. E & F images demonstrate mild caudate
atrophy and mild putaminal atrophy with peripheral high signal rim on T2W. Clinically, patient has dystonia but no parkinsonism.
Fig. 3. Caudate atrophy. Note the linear rather than the normal convex outline of the caudate in relation to the lateral ventricle.
34
L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
Fig. 4. Neuronal loss and astrogliosis of the putamen. (A) H and E stains. (B) Glial fibro fibrillary acidic protein stain.
observations are neurological evaluations and videotape
recordings. Wilhelmsen et al. [8] observed the presence
of both parkinsonism and dystonia in the family they
described from Iloilo in 1991.
An attempt to correlate the province of origin, age of
onset, severity of the disease, and the dystonic involvement
was done, but failed to show any significant difference;
suggesting that the XDP from Panay Island did not vary
among Filipinos. Analysis of the families revealed some
intrafamilial variation in the dystonic movements, however,
within the same kindred there was some commonality, i.e.
predominantly oromandibular in families #96, 38 and 7 and
leg dystonia in families #48, 16 and 14 (XDP registry).
2.2. Treatment
Different forms of anticonvulsants, antihistamines,
anticholinergics, antiparkinsonian and antipsychotic
drugs have shown no consistent beneficial effects [2].
Recently, the use of botolinum toxin has been tried and
was found beneficial in providing temporary relief of
focally impaired areas such as lingual or oromandibular
dystonia in generalized cases. The effects, however, were
not consistent and lasting. The use of muscle afferent
block utilizing lidocaine and ethanol is currently under
investigation.
Surgical treatment (thalamotomy in four, cerebellar
implantation in one) provided partial but no lasting relief.
One had residual hemiparesis. The case with implantation
became infected and developed an abscess causing his death
[1]. Two XDP cases had undergone pallidotomy in the
United States with unsuccessful results [9]. One died 48 h
after surgery.
2.3. Diagnostic studies
Laboratory, metabolic and biochemical studies of XDP
cases have not revealed any particular abnormality [2].
Electroencephalograph (EEG) and EMG studies in some
patients showed no specific abnormalities.
Few cases were able to undergo imaging studies since
only those in Metro Manila have access to more modern
facilities. Thirty-two had computed tomography (CT scan)
and 16 had magnetic resonance imaging (MRI) studies.
2.4. Magnetic resonance imaging
MRI findings in XDP are based on 16 male XDP cases,
ranging in age from 27 to 68 years. In 10 of 16 patients,
there is none or mild atrophy of the caudate nuclei and the
putamen. However, there are bilateral curvilinear increases
in signal intensity of the rims of the putamen on T2
weighting in all 10 patients. Clinically, all 10 of these
patients are in the earlier stages of disease when dystonic
features predominate and parkinsonism is absent (Fig. 2).
The pattern of an outer rim of high signal in the putamen has
been described previously in other diseases such as in
Wilson’s disease [10].
In six of the 16 patients, there is a bilateral and
symmetric, moderate to severe atrophy of the putamen
and heads of the caudate nuclei, associated with ex vacuo
dilatation of the frontal horns. The residual putamen
demonstrates a slit-like appearance with markedly increased
L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
35
Fig. 5. Family #38 showing 2 affected males in the 2nd generation (II), and 13 affected males in the 4th generation (IV).
signal intensity. Clinically, these patients are in the later
stages of disease, when parkinsonism dominates or when
parkinsonism coexists with dystonia. A similar MRI pattern
has previously been described for juvenile Huntington’s
disease [11].
2.5. Positron emission tomography
Eidelberg et al. [12] reported on three XDP (lubag) cases
with positron emission tomography (PET) studies. In all
three patients a selective reduction in normalized striatal
glucose metabolism (rCMRGIc/GMR) was observed compared with 15 normal volunteer subjects. Presynaptic
nigrostriatal function was assessed in these patients using
fluorodopa and PET. Striatal rate constants for fluorodopa
uptake were found to be in the normal range in all three
patients with lubag. These findings suggest that the
extrapyramidal manifestations of lubag are metabolically
localized to the striatum and that clinical parkinsonism in
these patients may be secondary to extranigral factors.
Waters et al. [5] reported PET studies in two XDP cases.
Fluorodopa PET in both the man and his affected cousin
revealed reduced striatal uptake rate constants consistent
with nigrostriatal involvement.
2.6. Pathology
Neuropathology of XDP is based on the postmortem
examination of six brains, ages ranging from 42 to 59 years.
Duration of illness ranged from 3 to 23 years. All six brains
consistently showed varying degrees of atrophy of the
caudate nucleus and putamen (Fig. 3). The case with the
shortest duration of illness had almost grossly normal
appearing basal ganglia. The case with the longest duration
of illness showed marked atrophy of the putamen and
caudate with concave depression of the caudate in relation
to the lateral ventricle. Neuronal loss and astrogliosis
involved the putamen and caudate nucleus including the
head, body, and tail (Fig. 4). The region of the nucleus
accumbens is generally the least affected. The degree of the
neuronal loss and the astrogliosis in each case paralleled the
degree of the gross atrophy.
The cerebral cortices, thalamus, subthalamic nuclei,
substantia nigra and pons were generally unremarkable.
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L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
Fig. 6. Family #16 showing 7 affected males in the 4th generation (IV).
Altrocchi and Forno [13] and Waters et al. [9] each,
published one neuropathologic case report of Filipinos with
XDP showing caudate and putamenal atrophy.
2.7. Genetics
The high rate of dystonia in Panay (five per 100,000
population) is indicative of a genetic founder effect. A
single mutation occurring in a common ancestor may have
been carried on in this geographic isolate owing to the
genetically non-lethal nature of the disorder. This theory is
supported by knowledge of several individuals with the
disease, living elsewhere in the Philippines and in the US
whose mothers or maternal ancestors originated from
Panay. The identification of the XDP gene has been pursued
using the positional cloning approach which facilitates the
isolation of the gene on the basis of its map position alone
even without the knowledge of its defective gene product. It
is largely dependent on the availability of polymorphic
markers that are linked to the disease, i.e. loci markers,
which lie close to the disease gene in the same chromosome.
The alleles in these loci will tend to pass together in each
gamete. By interference, if the marker locus is known then
the disease gene can be mapped to that region base pairs;
physical mapping can start with construction of a YAC
config map followed by gene isolation, expression and
characterization of the gene product.
Fig. 5 (Family #38) is an example of an updated
pedigree, previously reported by Lee et al. (1976) [2] in
“Torsion Dystonia in Panay, Philippines” with 28 patients,
all male, belonging to six families which indicated that the
disease under study is X-linked. Torsion dystonia was
previously described as autosomal recessive or dominant
[14].
Another pedigree illustration is Fig. 6 (Family #16).
There were seven affected males in four generations with
four brothers and onset mostly in the third and fourth decade
of life.
The X-linked inheritance pattern was firmly established
in Ref. [15] in a study of 21 families, 36 males, 17 of the
kindreds with family history of dystonia. There was no male
to male transmission.
Family linkage analysis with polymorphic DNA markers
that span the X chromosome made possible assignment of
the XDP gene to subchromosomal locations. Kupke et al.
[16] studied seven families with living torsion dystonia
patients and obligate carriers by using linkage analysis with
X chromosome (Xq21). Wilhelmsen et al. [8] in their study
L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
37
Fig. 7. Schematic diagram showing the time-wise development in the physical mapping of the XDP gene in the x chromosome until the approximation of the
locus to a candidate interval of ,350 kb segment.
of a large Filipino family with eight affected men in three
generations (total of 51 individuals), used DNA markers—
34 RFLP markers and one CA repeat polymorphism which
span Xp11.22 to Xq21.31 and reported that the XDP gene is
located in the pericentromeric region of the X chromosome.
On the other hand, linkage disequilibrium studies [17]
where frequencies of alleles for tightly linked markers in
affected individuals differed from the rest of the normal
population contributed to further narrowing of the suballocation in the X chromosome to Xq13. They studied 47
unrelated families with affected and unaffected members of
a three-generation XDP pedigree and 105 unrelated normal
Filipino male controls. They used polymorphic dinucleotide
tandem repeats (DNTRs) from Xq13-derived YACs (that
encompass either PGK1 or the proximally adjacent locus
DXS56). DNTR locus 4548-7 (locus DXS56) recombination event was observed and therefore indicated that DNTR
locus 4548-7 is a distal flanking marker. Muller et al. [18]
narrowed the approximate location to 3.0 Mb that is flanked
by DXS106 and DXS559 using short tandem repeat
polymorphism at six loci through linkage disequilibrium
and haplotype analysis.
Haberhausen et al. [19] were able to assign DYT3 to a
small region within a 1.8 Mb YAC contig constructed of
Xq13.1 (1.8 Mb) that included loci DXS 453, DXs348,
IL2R gamma, GJB1, CCG1 and DX559 using nine
sequence-tagged sites (STS) and four short tandem repeat
polymorphic markers and was able to further pinpoint the
gene location to within 1 Mb (DXS7117 –DXS1124). The
latest study is that of Nemeth’s group [20] who mapped
the XDP gene to a , 350 kb locus in the DXS7117–
DXS559 region. They have constructed a sequence ready
contig of 700 kb spanning the region where nine genes and
novel ESTs have been mapped. They have already excluded
two of these genes as the cause of XDP.
Fig. 7 is a schematic diagram showing the time-wise
development in the physical mapping of the XDP gene in
the X chromosome until the approximation of the locus to a
candidate interval of , 350 kb segment.
3. Discussion and summary
XDP defies the generalities in basal ganglia lesions. It is
known that the manifestation of basal ganglia lesions in
childhood is dystonia as exemplified by familial doparesponsive dystonia or juvenile parkinsonism [21]. On the
other hand, basal ganglia lesions in adulthood presents as
parkinsonism. XDP starts as focal dystonia in the third or
fourth decade spreads and generalizes from 2 to 5 years;
38
L.V. Lee et al. / Parkinsonism and Related Disorders 9 (2002) 29–38
stabilizes and becomes less severe from the 10th to 15th
year and is replaced by a parkinsonian picture beyond the
15th year. The movements in XDP are consistent with the
following clinical features of dystonia [22]. (a) The speed of
contraction may be slow or rapid and sustained at the peak
of movement. (b) There is a directional or posture assuming
character in the contractions consistent with dystonia. (c)
The movements start focally and spreads to other regions
until it generalizes. (d) It is aggravated by stress, fatigue and
some specific activities but can also be improved by some
movements as in paradoxical dystonia, rest, sleep and
hypnosis. (e) Sensory tricks which lessen contractions are
also observed in XDP.
XDP was initially included among the primary
dystonias before the parkinsonian features were fully
recognized. It was because of this that the gene
assignment of DYT3 was applied to XDP. Later, inspite
of the subsequent development of signs suggestive of
heredo-degenerative dystonia, the DYT3 gene nomenclature remained.
While following the XDP patients through the years,
the features of XDP not consistent with primary dystonia
became evident. One is the presence of parkinsonian
features either preceeding, in association or following the
dystonia. Second, dystonia occurred most often at rest
rather than with action. Third, the site of onset did not fit
the usual pattern such as leg onset in an adult and rapid
progression to generalization. Fourth, brain imaging and
neuropathology demonstrated atrophy of the caudate and
pallidum. The PET scan findings likewise suggested
involvement of the striatum. The present report has
documented the neuropathology previously reported in
Filipino XDP cases, however, caudate and putamenal
atrophy were only seen in long standing cases with
obvious Parkinsonian features.
To date, no neurohistochemical analysis have been made
on XDP cases but it is attractive to theorize that at the time
when dystonia manifests, there is marked activity of
tyrosine hydroxylase at the terminals of the nigrostriatal
dopamine (NS-DA) neurons although they are already in the
third and fourth decades of life. It is possible that as the
decrement in the NS-DA activities occurred, as expected
with age variation (usually in the first three decades),
Parkinsonism replaces the dystonia.
The location of the degenerative process may also
modify the motor manifestations; depending on whether the
direct or indirect pathway is affected. The direct pathway,
located in the ventral area of the striatum, matures earlier,
while the indirect pathway, in the dorsal area, matures later.
Functional MRI and PET studies should help clarify the
issues, and results of neurohistochemical investigations may
define it better. The picture of XDP might then be
understood while awaiting the genetic answers and the
definition of the protein defect.
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